SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

Francesco Ciscato; Marco Sciacovelli; Gianmarco Villano; Cristian Turato; Paolo Bernardi; Andrea Rasola; Patrizia Pontisso

doi:10.18632/oncotarget.1411

SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I

Oncotarget. 2014 May 15;5(9):2418-27. doi: 10.18632/oncotarget.1411.

Authors

Francesco Ciscato¹, Marco Sciacovelli, Gianmarco Villano, Cristian Turato, Paolo Bernardi, Andrea Rasola, Patrizia Pontisso

Affiliation

¹ CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Padova, Italy;

Abstract

SERPINB3 (SB3) is a serine protease inhibitor overexpressed in several malignancies of epithelial origin, including primary liver cancer, where it inhibits apoptosis through poorly defined mechanisms. In the present study we analyze the effect of SB3 on hepatoma cell death elicited by a panel of chemotherapeutic agents. We report that SB3 shields cells from the toxicity of drugs with a pro-oxidant action such as doxorubicin, cisplatin and EM20-25. The rapid rise in ROS levels prompted by these compounds causes opening of the mitochondrial permeability transition pore (PTP), irreversibly committing cells to death. We find that a fraction of SB3 locates in mitochondrial inner compartments, and that this mitochondrial fraction increases under conditions of oxidative stress. Mitochondrial SB3 inhibits ROS generation and the ensuing PTP induction and cell death through an inhibitory interaction with respiratory Complex I. These findings identify a novel mechanism of action of SB3 that contributes to tumor cell resistance to anti-neoplastic drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm / metabolism*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Blotting, Western
Calcium Signaling
Carcinoma, Hepatocellular / drug therapy
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Cell Proliferation / drug effects
Drug Resistance, Neoplasm
Electron Transport Complex I / antagonists & inhibitors*
Electron Transport Complex I / metabolism
Humans
Immunoprecipitation
Liver Neoplasms / drug therapy
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Mitochondria / drug effects
Mitochondria / metabolism*
Mitochondria / pathology
Mitochondrial Membrane Transport Proteins / drug effects
Mitochondrial Permeability Transition Pore
Oxidation-Reduction
Oxidative Stress / drug effects*
Reactive Oxygen Species / metabolism
Serpins / metabolism*
Tumor Cells, Cultured

Substances

Antigens, Neoplasm
Antineoplastic Agents
Mitochondrial Membrane Transport Proteins
Mitochondrial Permeability Transition Pore
Reactive Oxygen Species
Serpins
squamous cell carcinoma-related antigen
Electron Transport Complex I